Numerous studies on the function of the opioid receptor-like (ORL1) receptor and its endogenous peptide ligand, nociceptin, have been performed in the central nervous system (CNS), yet few studies have focused on their functions in the peripheral nervous system. Our preliminary data show that ORL1 receptors are expressed in peripheral sensory and sympathetic neuronal ganglia and that nociceptin plays an important role in synovial inflammatory and nociceptive processes via effects on peripheral sensory and sympathetic neuron terminals. We have recently shown that the regulation of prepronociceptin gene transcription is regulated by cAMP, glucocorticoids and estrogen. We propose to expand our preliminary studies to perform a comprehensive evaluation of the function of nociceptin and the ORL1 receptor in synovial inflammation and pain. The presence of prepronociceptin mRNA will be determined in peripheral neuronal ganglia and neuronal localization of ORL1 receptor and prepronociceptin mRNA will be identified using in situ hybridization techniques. Changes in neuronal expression of the ORL1 receptor and prepronociceptin mRNA and changes in ORL1 receptor protein and nociceptin peptide levels will be studied in rat models of chronic joint inflammation and nerve injury. The effect of steroid hormone treatment on mRNA and protein expression will be determined. Our preliminary studies demonstrate nociceptin's ability to enhance sympathetically mediated synovial inflammation. Mechanisms underlying this pro-inflammatory effect of nociceptin will be determined using plasma extravasation as a measure of inflammation. Furthermore, the ability of nociceptin to modulate other synovial inflammatory pathways will be studied. Lastly, nociceptin has been shown to produce differing responses on nociceptive pathways in the CNS. Specifically, nociceptin has hyperalgesic properties in brain, whereas intrathecal administration results in an anti-hyperalgesic effect at the spinal cord level. We hypothesize that nociceptin activation of the ORL1 receptor on sensory afferent terminals modulates peripheral nociceptive mechanisms. Our preliminary results indicate that infra-articular nociceptin enhances synovial nociceptive mechanisms as measured by capsaicin-induced dorsal horn c-Fos levels. The functional role of nociceptin in peripheral nociceptive mechanisms will be assessed by using a model of mechanical hyperalgesia in the rat knee joint. Recently, ORL1 receptor antagonists have been developed and these agents will be used to determine the significance of endogenous nociceptin in chronic synovial inflammation and hyperalgesia.